Interferon targeted therapies in systemic lupus erythematosus

Type I interferons secreted by plasmacytoid dendritic cells (pDCs) play a crucial role in the pathogenesis of systemic lupus erythematosus by driving the formation of autoantibodies against nuclear debris. Inherited mutations causing activation of the Type I interferon pathway result in a phenotype of systemic autoimmunity which resembles some of the manifestations of lupus. Patients with lupus have increased expression of interferon-stimulated genes in the peripheral blood mononuclear cells which is abrogated following immunosuppressive treatment. Recent therapeutic approaches have involved monoclonal antibodies directly targeting interferon alpha (sifalimumab, rontalizumab) or the use of interferon alpha kinoid to stimulate endogenous production of anti-interferon antibodies in lupus. Other drugs used in lupus such as hydroxychloroquine and bortezomib also reduce circulating levels of type I interferons. Newer therapeutic strategies being investigated in preclinical models of lupus that reduce the production of Type I interferons include dihydroartemisinin, Bruton's tyrosine kinase antagonists, Bcl-2 antagonists and sphingosine-1 phosphate agonists.